Process for the preparation of ospemifene

ABSTRACT

The present invention is related to the process for the preparation ospemifene or (Z)-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol (I) and to intermediate compounds used in the process.

CROSS REFERENCE TO RELATED APPLICATION

This application is a National Stage entry under 35 USC 371 ofPCT/FI2013/000039, filed on Oct. 17, 2013, which is a nonprovisionalapplication of U.S. Provisional Patent Application No. 61/716,171, filedon Oct. 19, 2012.

FIELD OF THE INVENTION

The invention is related to a process for the preparation ospemifene andto intermediate compounds used in the process.

BACKGROUND OF THE INVENTION

Ospemifene or (Z)-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanolis represented by formula (I):

Ospemifene is an estrogen receptor agonist/antagonist currentlyinvestigated e.g. for the treatment of vulvar and vaginal atrophy due tomenopause.

Preparation of ospemifene starting fromZ-4-(4-hydroxy-1,2-diphenyl-but-1-enyl)phenol has been described in WO96/07402. Use of McMurry coupling reaction for the manufacture ofospemifene has been described in WO 2008/099059 and WO 2011/089385.These methods suffer from the drawback that large amounts of expensivereagents or solvents, such as titanium tetrachloride, LiAlH₄, and2-Me-THF, are needed:

Thus, it is desirable to provide an improved method for producingospemifene in high yield and purity the method also being economicallyfeasible and suitable for use in a large scale.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of acompound of formula (I)

which process comprises

(a) reacting a compound of formula (III)

wherein R is a protecting group tolerant to Grignard or otherorganometallic reagents, with phenylmagnesium halide to produce acompound of formula (IV)

wherein R is as defined above, and

(b) treating the compound of formula (IV) with hydrochloric acid toproduce a compound of formula (V)

wherein R is as defined above, and

(c) cleaving the ester bond of a compound of formula (V) wherein R is asdefined above, to give a compound of formula (I).

In another aspect, the present invention provides a process for thepreparation of a compound of formula (I) comprising, the step oftreating the compound of formula (IV), wherein R is a protecting grouptolerant to Grignard or other organometallic reagents, with hydrochloricacid to produce a compound of formula (V), and cleaving the ester bondof a compound of formula (V) to give a compound of formula (I).

The invention is also directed to novel compounds of formula (III) and(IV) wherein R is t-butyl, adamantyl or 2,4,6-trimethylphenyl.

DETAILED DESCRIPTION OF THE INVENTION

The term “lower alcohol” means C₁₋₅ alcohol, preferably C₁₋₄ alcohol.Representative examples include methanol, ethanol, isopropanol andbutanol, particularly preferred is methanol and ethanol.

In accordance with the present invention the compound of formula (III)

wherein R is a protecting group tolerant to Grignard or otherorganometallic reagents, is reacted with phenylmagnesium halide toproduce a compound of formula (IV)

wherein R is as defined above.

The above reaction is based on the nucleophilic addition of aphenylmagnesium halide (Grignard reagent), such as phenylmagnesiumchloride or phenylmagnesium bromide, to the carbonyl group of thecompound of formula (III). The reaction is carried out in suitablesolvent, such as diethyl ether or THF, under nitrogen atmosphere. Thereagents are suitably added at room temperature and the mixture isheated, for example to about 60° C. The reaction is typically completedwithin about 2-3 hours. The reaction can be quenched e.g. with additionof saturated NH₄Cl-solution. Phenylmagnesium halide reagent is attypically used in molar excess, e.g. in 1.5-2 molar equivalents percompound of formula (III). The resulting compound of formula (IV) can beisolated, if desired, by evaporation of the solvents and subsequentcrystallization or the crude compound can be forwarded directly to thenext step.

In the next step the compound of formula (IV) is subjected todehydration and ring-opening reaction by treating it with hydrochloricacid to produce the ester compound of formula (V).

Thus, the compound of formula (IV) is dissolved in a suitable solventsuch as dichloromethane (DCM) or toluene and this solution is addedslowly to aqueous HCl solution, such as 30% HCl solution. The reactionis suitably carried out at room temperature. The reaction is typicallycompleted within less than one hour.

The resulting ester of formula (V) is particularly suitable for beingisolated and purified by crystallization before its use in the nextreaction step. Thus, after completion of the ring opening reaction thereaction mixture can be poured on saturated NaHCO₃ solution and theorganic phase is recovered. The organic phase is preferably evaporatedand the crystallization solvent is added. Suitable crystallizationsolvents include plain lower alcohols, such as methanol and ethanol.Particularly suitable crystallization, solvents are methanol or ethanolessentially in the absence of water, thereby giving the ester of formula(V) in high yield and purity. The mixture of crystallization solvent andcrude ester of formula (V) is stirred and suitably heated to achievedissolution. The mixture may then be cooled to about 40° C. and seededwith the desired Z-isomer. Cooling is continued over a period of time(preferably slowly, e.g. over more than one hour) to room temperature orbelow, e.g. below 15° C., in order to achieve crystallization. Themixture is suitably stirred in this temperature for more than 3 hours,e.g. for 12 hours. The crystalline ester of formula (V) is filtered,washed and dried preferably under reduced pressure. The chemical purityof the crystallized compound of formula (V) is at this stage typicallyhigher than 92% and the amount of E-isomer less than 5%. The end productmay be further recrystallized if desired.

Compounds of formula (III) can be prepared using the methods known inthe art.

For example, compound of formula (III) can be suitably prepared byreacting a compound of formula (II)

with a compound of formula X₁—CH₂—CH₂—X₂, wherein X₁ and X₂ is a leavinggroup and R is a protecting group tolerant to Grignard or otherorganometallic reagents. Suitable leaving groups X₁ and X₂ include, butare not limited to, halogens, para-toluenesulfonate (CH₃C₆H₄SO₂O—),methanesulfonate (CH₃SO₂O—) and trifluoromethanesulfonate (CF₃SO₂O—)groups. According to one embodiment of the invention X₁ and X₂ arehalogens, in particular X₁ is Br and X₂ is Cl. The reaction between thecompound of formula (II) and the compound of formula X₁—CH₂—CH₂—X₂ issuitably carried out in the presence of a phase transfer catalyst (PTC),such as quaternary ammonium or phosphonium salts. Examples of phasetransfer catalyst include tetrabutylammonium hydrogensulfate (TBAHS),benzyltrimethylammonium chloride and hexadecyltributylphosphoniumbromide. Thus, compound of formula (II) is dissolved in suitable solventsuch as toluene under nitrogen atmosphere at room temperature followedby the addition of phase transfer catalyst such as TBAHS and aqueousNaOH solution (e.g. 50% NaOH solution) to the reaction mixture. Theresulting two-phase system is stirred vigorously and the compound offormula X₁—CH₂—CH₂—X₂ is added dropwise. The reaction is typicallycompleted within 12 hours. The organic phase is isolated, washed,filtered, dried and evaporated to obtain the compound of formula (III).

Alternatively, the reaction between the compound of formula (II) and thecompound of formula X₁—CH₂—CH₂—X₂ can be carried out in an organicsolvent, such as DMSO, DMF or THF, in the presence of a base such asNaH, K-, Na- or LiOBu-t, or corresponding carbonates.

Compounds of formula (II) can be prepared using the methods known in theart.

For example, compound of formula (II) can be suitably prepared byreacting a compound of formula (VI)

wherein R is C₁₋₅ alkyl or an optionally substituted phenyl, with2-phenylacetic acid. Typically, the reaction is catalyzed by a Brønstedacid, such as polyphosphoric acid (PPA). Thus, to warmed PPA is addedcompound of formula (VI) and 2-phenylacetic acid. After stirring forabout 3 h, water is added and the mixture, is stirred further, at roomtemperature for about 2 h. The precipitated compound of formula (II) isfiltered, washed and dried, and, if desired, recrystallised fromsuitable solvent, such as hexane/isopropanol (1:1).

According to one embodiment of the invention, particularly suitablecompounds of formula (II), (III), (IV), (V) and (VI) are those wherein Ris t-butyl, adamantyl or 2,4,6-trimethylphenyl. Particularly preferredcompounds of formula (II), (III), (IV), (V) and (VI) are those wherein Ris t-butyl.

The compound of formula (I) (ospemifene) is obtained by subjecting thecompound of formula (V) to cleavage of the ester bond (dashed bondbelow) of the compound of formula (V)

such that the hydroxyl group of ospemifene is formed.

The cleavage of the ester bond of the compound of formula (V) can becarried out by using well known methods such hydrolysis or a reductivecleavage.

Hydrolysis of the ester bond of the compound of formula (V) can becatalysed by a base or acid. A base catalysed hydrolysis is particularlypreferred. The base catalysed hydrolysis can be carried in a suitablesolvent such as aqueous THF or aqueous THF/MeOH mixture in the presenceof a suitable base, such as NaOH or LiOH at room temperature for a timesufficient to complete the hydrolysis. When the hydrolysis is carriedout at room temperature, the reaction is completed typically within 12hours or less. Thereafter, water and suitable organic solvent such asEtOAc is added and the organic phase is washed, dried, filtered andconcentrated. Ospemifene can be conveniently isolated from the residueby crystallization from a suitable crystallization solvent. Preferredsolvents for crystallization are C₁₋₅ alcohols, particularly methanol,ethanol or isopropanol, or aqueous. C₁₋₅ alcohols such as aqueousmethanol (e.g. 80% or 90% methanol).

Reductive cleavage of the ester bond of the compound of formula (V) toobtain ospemifene can be carried out in the presence of a reducing agentsuch as lithium aluminium hydride in a suitable organic solvent such astoluene, THF, hexane or xylene or mixture thereof. The reaction issuitably carried out at room temperature and under nitrogen atmosphere.The reaction may be suitably quenched by addition of saturatedNH₄Cl-solution. Organic phase is washed, dried, filtered andconcentrated. Ospemifene can be conveniently isolated from the residueby crystallization from a suitable crystallization solvent as describedabove:

The invention is further illustrated by the following non-limitingexamples.

EXAMPLES Example 1 Preparation of 2-phenoxyethyl pivalate

2-Phenoxyethanol (50 g, 0.362 mol) was dissolved in dichloromethane (500ml) and the solution was cooled to 0-5° C. Triethylamine (101 ml, 0.724mol) was added to the cooled solution followed by pivaloyl chloride(53.5 ml, 0.434 mol) maintaining the temperature, below 5° C. Afteradditions the mixture was stirred at 5° C. for 30 min and at roomtemperature for 12 h. The reaction was quenched by addition of 1MHCl-solution (300 ml) and stirred vigorously. The phases were separatedand organic phase was washed with saturated NaHCO₃-solution (2×150 ml),water (1×100 ml) and brine (1×100 ml). After drying (Na₂SO₄) andfiltration the solvent was evaporated yielding the title compound (76.78g, 0.345 mol, 95%) as a yellow oil. ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm):7.31-7.27 (2H, m, ArH), 6.96-6.93 (3H, m, ArH), 4.34 (2H, m,CH₂CH₂OPiv), 4.19 (2H, m, ArOCH₂CH₂), 1.13 (9H, s, 3×Me). ¹³C-NMR (100MHz, DMSO-d₆) δ (ppm): 177.7, 158.7, 130.1, 121.1, 114.9, 66.1, 62.9,38.5, 27.6.

Example 2 Preparation of 2-(4-(2-Phenylacetyl)phenoxy)ethyl pivalate

Polyphosphoric acid (PPA) (250 g) was charged to a reaction vessel andwarmed to 50° C. (bath temperature) with mechanical stirring.2-Phenylacetic acid (30.6 g, 0.225 mol) was added to PPA followed by2-phenoxyethyl pivalate (50 g, 0.225 mol). After 3 hours TLC and HPLCindicated full conversion and water (1000 ml) was added. The mixture wasstirred at room temperature for 2 h. The precipitated product wasfiltered and washed with water (300 ml). After drying in vacuo the crudeproduct (65 g) was re-crystallized with hexane/i-PrOH 1:1 yielding thetitle compound as slightly yellow solid (51.49 g, 0.151 mol, 67%).¹H-NMR (400 MHz, DMSO-d₆) δ (ppm): 8.02 (2H, d, J=9.2 Hz, ArH),7.32-7.22 (5H, m, ArH), 7.07 (2H, d, J=8.8 Hz, ArH), 4.37 (2H, m,CH₂CH₂OPiv), 4.31 (2H, s, ArCH₂CO), 4.3 (2H, m, ArOCH₂CH₂), 1.12 (9H, s,3×Me). ¹³C-NMR (100 MHz, DMSO-d₆) δ (ppm): 196.4, 177.7, 162.6, 135.8,131.2, 129.9, 129.8, 128.7, 126.8, 114.8, 66.5, 62.7, 44.8, 38.6, 27.2.

Example 3 Preparation of 2-(4-(1-Phenylcyclopropanecarbonyl)phenoxyethyl pivalate

2-(4-(2-Phenylacetyl)phenoxy)ethyl pivalate (15 g, 44.1 mmol) wasdissolved in nitrogen bubbled toluene (150 ml) and stirred undernitrogen atmosphere for 10 min at room temperature. Tetrabutylammoniumhydrogensulfate (1.496 g, 4.41 mmol) catalyst was added to the stirredsolution followed by 50% NaOH-solution (60 ml, 1137 mmol). The two-phasesystem was stirred vigorously for 10 min. 1-Bromo-2-chloroethane (9.17mL, 110 mmol) was dissolved in toluene (35 ml) and added dropwise to thestirred reaction mixture. After 12 hours the starting material wasconsumed and water (100 ml) was added. The phases were separated and theaqueous layer was extracted with toluene (50 ml). The combined toluenephases were washed with water (100 ml) and brine (100 ml). After drying(Na₂SO₄) and filtration toluene was removed in vacuo. Crude titlecompound (15.39 g, 42 mmol, 95%) was obtained as sticky brown oilcontamined with 15% of O-alkylated by-product. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 7.80 (2H, d, J=9.2 Hz, ArH), 7.26-7.16 (5H, m, ArH), 6.77 (2H, d,J=8.8 Hz, ArH), 4.37 (2H, t, J=4.8 Hz, CH₂CH₂OPiv), 4.15 (2H, t, J=5.0Hz, ArOCH₂CH₂), 1.60 (2H, AB-system, J=4.4 Hz, CH₂CH₂), 1.32 (2H,AB-system, J=4.4 Hz, CH₂CH₂), 1.17 (9H, s, 3×Me). ¹³C-NMR (100 MHz,CDCl₃) δ (ppm): 198.6, 178.9, 162.1, 141.7, 132.3, 130.2, 129.1, 127.9,126.8, 114.2, 67.0, 62.8, 39.2, 35.0, 27.5, 16.1.

Example 4 Preparation of(Z)-2-(4-(4-Chloro-1,2-diphenylbut-1-en-1-yl)-phenoxy)ethyl pivalate

Crude 2-(4-(1-Phenylcyclopropanecarbonyl)phenoxy)ethyl pivalate (15.3 g,41.8 mmol) was dissolved in tetrahydrauran (THF) (200 ml) under nitrogenwith stirring. 1 M THF-solution of phenylmagnesium chloride (35.5 ml, 71mmol) was added dropwise to the solution at room temperature. Afteraddition the reaction was warmed to 60° C. and kept at this temperaturefor two hours. The reaction was quenched by addition of saturatedNH₄Cl-solution (300 ml). The pH was adjusted to 4 with 5% HCl-solutionand THF-phase was separated. The aqueous phase was extracted withdichloromethane (2×75 ml), combined with THF-phase, and washed withwater (100 ml) and brine (100 ml). After drying (Na₂SO₄) and filtrationthe solvents were evaporated and crude cyclopropylcarbinol intermediate(21 g) was directly submitted to the ring-opening step. The crudecyclopropylcarbinol intermediate was dissolved in dichloromethane (DCM)(150 ml) and treated with 30% HCl-solution (120 ml). After 60 min thedehydration and ring-opening was complete and reaction mixture waspoured on saturated NaHCO₃-solution (350 ml). The phases were separatedand DCM-phase was washed with water (100 ml) and brine (100 ml). Afterdrying (Na₂SO₄) and filtration the solvent was evaporated. The residuewas dissolved in boiling methanol, cooled to 40° C. and seeded. Afterstirring at room temperature (12 h) the precipitated title compound wasfiltered and washed with cold MeOH. The title compound was obtained as awhite solid (5.4 g, 11.7 mmol, 28% over two steps). ¹H-NMR (400 MHz,CDCl₃) δ (ppm): 7.39-7.13 (6H, m, ArH), 6.79 (2H, d, J=8.8 Hz, ArH),6.56 (2H, d, J=8.8 Hz, ArH), 4.31 (2H, t, J=4.4 Hz, CH₂CH₂OPiv), 4.04(2H, t, J=4.8 Hz, ArOCH₂CH₂), 3.41 (2H, t, J=7.6 Hz, ClCH₂CH₂), 2.92(2H, t, 1=7 0.6 Hz, ClCH₂CH₂), 1.17 (9H, s, 3×Me). ¹³C-NMR (100 MHz,CDCl₃) δ (ppm): 178.5, 156.8, 142.8, 141.6, 140.9, 135.3, 135.2, 131.7,129.5, 129.4, 128.4, 128.2, 127.0, 126.6, 113.6, 65.7, 62.7, 42.8, 38.7,38.6, 27.1.

Example 5 Preparation of(Z)-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)-phenoxy]ethanol (ospemifene)by Base Hydrolysis of Pivaloyl-Group

(Z)-2-(4-(4-Chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl pivalate (1g, 2.16 mmol) was dissolved in THF (8 ml) followed by addition of MeOH(1 ml) and water (1 ml). Sodium hydroxide (0.1 g, 2.5 mmol) was added inone portion and the reaction was stirred at room temperature for 12 h.After completion of the reaction the mixture was partitioned betweenwater (20 ml) and EtOAc (20 ml). Organic phase was washed with water (20ml) and brine (20 ml), dried (Na₂SO₄), filtered and concentrated. Theresidue was crystallized from i-PrOH yielding ospemifene (0.29 g, 35%)as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ (ppm): 7.37 (2H, t, J=8 Hz,ArH), 7.29 (3H, t, J=7.2 Hz, ArH), 7.20 (2H, t, J=7.6 Hz, ArH),7.16-7.13 (3H, m, ArH), 6.80 (2H, d, J=8.8 Hz, ArH), 6.57 (2H, d, J=8.8Hz, ArH), 3.94 (2H, t, J=4.4 Hz, ArOCH₂CH₂OH), 3.87 (2H, m,ArOCH₂CH₂OH), 3.42 (2H, t, J=7.2 Hz, ClCH₂CH₂), 2.92 (2H, t, J=7.2 Hz,ClCH₂CH₂), 1.95 (1H, t, J=6.4 Hz, OH). ¹³C-NMR (100 MHz, CDCl₃) δ (ppm):157.2, 143.2, 142.1, 141.3, 2×135.7, 132.2, 130.0, 129.8, 128.8, 128.7,127.4, 127.0, 113.9, 69.3, 61.8, 43.3, 39.0.

Example 6 Preparation of(Z)-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)-phenoxy]ethanol (Ospemifene)by Reductive Cleavage of Pivaloyl-Group

(Z)-2-(4-(4-Chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl pivalate (3.5g, 7.56 mmol) was dissolved in toluene (35 ml) and stirred undernitrogen for 5 min at room temperature. Lithium aluminium hydridesolution (1 M in THF) (7.56 ml, 7.56 mmol) was added dropwise to thereaction and the mixture was stirred at room temperature for 30 min.After HPLC indicated completion, the reaction was quenched by additionof saturated NH₄Cl-solution (75 ml). Additional amount of toluene (30ml) was added and the phases were separated. The organic phase waswashed with water (50 ml), brine (50 ml), dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was crystallized froth 90% MeOHyielding ospemifene (1.75 g, 61%) as a white solid.

The invention claimed is:
 1. A process of preparing a compound offormula (I)

which process comprises (a) reacting a compound of formula (III)

 wherein R is a protecting group tolerant to Grignard or otherorganometallic reagents, with phenylmagnesium halide, thereby obtaininga compound of formula (IV)

wherein R is as defined in formula (III), (b) treating the compound offormula (IV) with hydrochloric acid, thereby obtaining a compound offormula (V)

wherein R is as defined as in formula (III), and (c) cleaving the esterbond of the compound of formula (V), thereby obtaining the compound offormula (I).
 2. The process according to claim 1, wherein thephenylmagnesium halide is phenylmagnesium chloride.
 3. The processaccording to claim 1, further comprising isolating the compound offormula (V) by crystallization.
 4. The process according to claim 3,wherein the crystallization of the compound of formula (V) is from alower alcohol.
 5. The process according to claim 4, wherein the loweralcohol is methanol or ethanol.
 6. The process according to claim 1,wherein (c) cleaving the ester bond of the compound of formula (V) iscarried out by a base catalyzed hydrolysis or a reductive cleavage. 7.The process according to claim 6, wherein (c) cleaving the ester bondcomprises reductive cleavage in the presence of lithium aluminumhydride.
 8. The process according to claim 1, further comprisingisolating the compound of formula (I) by crystallization.
 9. The processaccording to claim 8, wherein isolating the compound of formula (I)comprises crystallizing the compound of formula (I) from C₁₋₅ alcohol orfrom a mixture of C₁₋₅ alcohol and water.
 10. The process according toclaim 1, wherein R is t-butyl, adamantyl or 2,4,6-trimethylphenyl. 11.The process according to claim 10, wherein R is t-butyl.
 12. The processaccording to claim 1, further comprising preparing the compound offormula (III) by reacting a compound of formula (II)

with a compound of formula X₁—CH₂—CH₂—X₂, wherein X₁ and X₂ are each aleaving group and R is a protecting group tolerant to Grignard or otherorganometallic reagents.
 13. The process according to claim 12, whereinX₁ is halogen and X₂ is halogen.
 14. The process according to claim 13,wherein X₁ is Br and X₂ is Cl.
 15. The process according to claim 12,wherein R is t-butyl, adamantyl or 2,4,6-trimethylphenyl.
 16. Theprocess according to claim 15, wherein R is t-butyl.
 17. The processaccording to claim 12, wherein reacting the compound of formula (II)with the compound of formula X₁—CH,—CH,—X₂ is carried out in thepresence of a phase transfer catalyst.
 18. The process according toclaim 17, wherein the phase transfer catalyst is tetrabutylammoniumhydrogensulfate (TBAHS).
 19. The process according to claim 12, furthercomprising preparing the compound of formula (II) by reacting a compoundof formula (VI)

wherein R is a protecting group tolerant to Grignard or otherorganometallic reagents, with 2-phenylacetic acid.
 20. The processaccording to claim 19, wherein R is t-butyl, adamantyl or2,4,6-trimethylphenyl.
 21. The process according to claim 20, wherein Ris t-butyl.
 22. A process of preparing a compound of formula (I)

the process comprising treating a compound of formula (IV)

 wherein R is a protecting group tolerant to Grignard or otherorganometallic reagents, with hydrochloric acid, thereby obtaining acompound of formula (V)

wherein R is as in formula (IV), and cleaving the ester bond of thecompound of formula (V), thereby obtaining the compound of formula (I).23. The process according to claim 2, wherein R is t-butyl, adamantyl or2,4,6-trimethylphenyl.
 24. The process according to claim 23, wherein Ris t-butyl.
 25. A compound of formula (III)

wherein R is t-butyl, adamantyL or 2,4,6-trimethylphenyl.
 26. Thecompound according to claim 25, wherein R is t-butyl.
 27. A compound offormula (IV)

wherein R is t-butyl, adamantyl or 2,4,6-trimethylphenyl.
 28. Thecompound according to claim 27, wherein R is t-butyl.
 29. The process ofclaim 3, wherein a chemical purity of the compound of formula (V)immediately after the crystallization is higher than 92%.
 30. Theprocess of claim 3, wherein the compound of formula (V) immediatelyafter the crystallization has a content of less than 5% of an E-isomerof the compound of formula (V).